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Irregular vestibular afferents exhibit significant phase leads with respect to angular velocity of the head in space. This characteristic and their connectivity with vestibulospinal neurons suggest a functionally important role for these afferents in producing the vestibulo-collic reflex (VCR). A goal of these experiments was to test this hypothesis with the use of weak galvanic stimulation of the vestibular periphery (GVS) to selectively activate or suppress irregular afferents during passive whole body rotation of guinea pigs that could freely move their heads. Both inhibitory and excitatory GVS had significant effects on compensatory head movements during sinusoidal and transient whole body rotations. Unexpectedly, GVS also strongly affected the vestibulo-ocular reflex (VOR) during passive whole body rotation. The effect of GVS on the VOR was comparable in light and darkness and whether the head was restrained or unrestrained. Significantly, there was no effect of GVS on compensatory eye and head movements during volitional head motion, a confirmation of our previous study that demonstrated the extravestibular nature of anticipatory eye movements that compensate for voluntary head movements. [ABSTRACT FROM AUTHOR]

Temporal lobe seizures in humans correlate with stereotyped electrophysiological patterns that can be reproduced in animal models to study the cellular and network changes responsible for ictogenesis. Seizure-like discharges that mimic seizure patterns in humans were induced in the entorhinal cortex of the in vitro isolated guinea pig brain by 3-min arterial applications of the GABAAreceptor antagonist bicuculline. The onset of seizure is characterized by a paradoxical interruption of firing for several seconds in principal neurons coupled with both enhanced interneuronal firing and increased extracellular potassium (Gnatkovsky et al. 2008). The evolution of action potential features from firing break to excessive and synchronous activity associated with the progression of seizure itself is analyzed here. We utilized phase plot analysis to characterize action potential features of entorhinal cortex neurons in different phases of a seizure. Compared with preictal action potentials, resumed spikes in layer II–III neurons (n = 17) during the early phase of the seizure-like discharge displayed 1) depolarized threshold, 2) lower peak amplitude, 3) depolarized voltage of repolarization and 4) decelerated depolarizing phase, and 5) spike doublettes. Action potentials in deep-layer principal cells (n = 8) during seizure did not show the marked feature changes observed in superficial layer neurons. Action potential reappearance correlated with an increase in extracellular potassium. High-threshold, slow-action potentials similar to those observed in the irregular firing phase of a seizure were reproduced in layer II–III neurons by direct cortical application of a highly concentrated potassium solution (12–24 mM). We propose that the generation of possibly nonsomatic action potentials by increased extracellular potassium represents a crucial step toward reestablish firing after an initial depression in an acute model of temporal lobe seizures. Resumed firing reengages principal neurons into seizure discharge and promotes the transition toward the synchronized burst firing that characterizes the late phase of a seizure. [ABSTRACT FROM AUTHOR]

Psychophysical studies show a slower response to changes in the specifically binaural input than to changes in the monaural input (binaural sluggishness). However, there is disagreement about the time course. Tracking changes in a target yields fast time constants, while detecting a constant target against a varying background yields the slowest. Changes in the binaural properties of a target are tracked up to high rates by cells in the midbrain. Indeed cells respond rapidly to a step change and then the firing rate slowly adapts. These experiments, though, are analogues of psychophysical experiments that give the faster time constants. Sluggishness should be more apparent physiologically in a binaural masking paradigm, detecting a short tone in a noise masker with a step change in masker correlation: the small change in firing rate due to the signal must be detected against the adapting firing rate change caused by the step change in the masker. However, in 40 inferior colliculus cells in the anesthetized guinea pig, in a direct analogue of the psychophysical masking paradigm, measuring thresholds for short tones across a transition in a binaural masker (e.g., from N0S0 to NπS0) provided little evidence of sluggishness within individual cells despite masking level differences in these cells comparable with previous data. Previous studies of physiological correlates of binaural masking level difference suggested that different psychophysical thresholds arise from different populations of cells. This suggests the hypothesis that sluggishness may result from a change in focus between the different populations of cells signaling threshold in different binaural configurations rather than within the intrinsic properties of the cells themselves. [ABSTRACT FROM AUTHOR]

In vitro studies performed on brain slices demonstrate that the potassium channel blocker 4-aminopyridine (4AP, 50 µM) discloses electrographic seizure activity and interictal discharges. These epileptiform patterns have been further analyzed here in a isolated whole guinea pig brain in vitro by using field potential recordings in olfactory and limbic structures. In 8 of 13 experiments runs of fast oscillatory activity (fast runs, FRs) in the piriform cortex (PC) propagated to the lateral entorhinal cortex (EC), hippocampus and occasionally to the medial EC. Early and late FRs were asynchronous in the hemispheres showed different duration [1.78 ± 0.51 and 27.95 ± 4.55 (SD) s, respectively], frequency of occurrence (1.82 ± 0.49 and 34.16 ± 6.03 s) and frequency content (20–40 vs. 40–60 Hz). Preictal spikes independent from the FRs appeared in the hippocampus/EC and developed into ictal-like discharges that did not propagate to the PC. Ictal-like activity consisted of fast activity with onset either in the hippocampus (n = 6) or in the mEC (n = 2), followed by irregular spiking and sequences of diffusely synchronous bursts. Perfusion of the N-methyl-D-aspartate receptor antagonist 2-amino-5-phosphonopentanoic acid (100 µM) did not prevent FRs, increased the duration of limbic ictal-like discharges and favored their propagation to olfactory structures. The AMPA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (50 µM) blocked ictal-like events and reduced FRs. In conclusion, 4AP-induced epileptiform activities are asynchronous and independent in olfactory and hippocampal-entorhinal regions. Epileptiform discharges in the isolated guinea pig brain show different pharmacological properties compared with rodent in vitro slices. [ABSTRACT FROM AUTHOR]

We have demonstrated that 4-aminopyridine-3-methanol (4-AP-3-MeOH), a 4-aminopyridine derivative, significantly restores axonal conduction in stretched spinal cord white-matter strips and shows no preference in restoring large and small axons. This compound is 10 times more potent when compared with 4-AP and other derivatives in restoring axonal conduction. Unlike 4-AP, 4-AP-3-MeOH can restore axonal conduction without changing axonal electrophysiological properties. In addition, we also have confirmed that 4-AP-3-MeOH is indeed an effective blocker of IAbased on patch-clamp studies using guinea pig dorsal root ganglia cells. Furthermore, we have also provided the critical evidence to confirm the unmasking of potassium channels following mechanical injury. Taken together, our data further supports and implicates the role of potassium channels in conduction loss and its therapeutic value as an effective target for intervention to restore function in spinal cord trauma. Furthermore, due to its high potency and possible low side effect of impacting electrophysiological properties, 4-AP-3-MeOH is perhaps the optimal choice in reversing conduction block in spinal cord injury compared with other derivatives previously reported from this group. [ABSTRACT FROM AUTHOR]

In the normal guinea pig, contralateral sound inhibits more than a third of ventral cochlear nucleus (VCN) neurons but excites <4% of these neurons. However, unilateral conductive hearing loss (CHL) and cochlear ablation (CA) result in a major enhancement of contralateral excitation. The response properties of the contralateral excitation produced by CHL and CA are similar, suggesting similar pathways are involved for both types of hearing loss. Here we used the neurotoxin melittin to test the hypothesis that this "compensatory" contralateral excitation is mediated either by direct glutamatergic CN-commissural projections or by cholinergic neurons of the olivocochlear bundle (OCB) that send collaterals to the VCN. Unit responses were recorded from the left VCN of anesthetized, unilaterally deafened guinea pigs (CHL via ossicular disruption, or CA via mechanical destruction). Neural responses were obtained with 16-channel electrodes to enable simultaneous data collection from a large number of single- and multiunits in response to ipsi- and contralateral tone burst and noise stimuli. Lesions of each pathway had differential effects on the contralateral excitation. We conclude that contralateral excitation has a fast and a slow component. The fast excitation is likely mediated by glutamatergic neurons located in medial regions of VCN that send their commissural axons to the other CN via the dorsal/intermediate acoustic striae. The slow component is likely mediated by the OCB collateral projections to the CN. Commissural neurons that leave the CN via the trapezoid body are an additional source of fast, contralateral excitation. [ABSTRACT FROM AUTHOR]

In the most commonly used cochlear prosthesis systems, temporal features of sound are signaled by amplitude modulation of constant-rate pulse trains. Several convincing arguments predict that speech reception should be optimized by use of pulse rates 2,000 pulses per second (pps) and by use of intracochlear electrode configurations that produce restricted current spread (e.g., bipolar rather than monopolar configurations). Neither of those predictions has been borne out in consistent improvements in speech reception. Neurons in the auditory cortex of anesthetized guinea pigs phase lock to the envelope of sine-modulated electric pulse trains presented through a cochlear implant. The present study used that animal model to quantify the effects of carrier pulse rate, electrode configuration, current level, and modulator wave shape on transmission of temporal information from a cochlear implant to the auditory cortex. Modulation sensitivity was computed using a signal-detection analysis of cortical phase-locking vector strengths. Increasing carrier pulse rate in 1-octave steps from 254 to 4,069 pps resulted in systematic decreases in sensitivity. Comparison of sine- versus square-wave modulator waveforms demonstrated that some, but not all, of the loss of modulation sensitivity at high pulse rates was a result of the decreasing size of pulse-to-pulse current steps at the higher rates. Use of a narrow bipolar electrode configuration, compared with the monopolar configuration, produced a marked decrease in modulation sensitivity. Results from this animal model suggest explanations for the failure of high pulse rates and/or bipolar electrode configurations to produce hoped-for improvements in speech reception. [ABSTRACT FROM AUTHOR]

Cochlear implant speech processors transmit temporal features of sound as amplitude modulation of constant-rate electrical pulse trains. This study evaluated the central representation of amplitude modulation in the form of phase-locked firing of neurons in the auditory cortex. Anesthetized pigmented guinea pigs were implanted with cochlear electrode arrays. Stimuli were 254 pulse/s (pps) trains of biphasic electrical pulses, sinusoidally modulated with frequencies of 10–64 Hz and modulation depths of –40 to –5 dB re 100% (i.e., 1–56.2% modulation). Single- and multiunit activity was recorded from multi-site silicon-substrate probes. The maximum frequency for significant phase locking (limiting modulation frequency) was ≥60 Hz for 42% of recording sites, whereas phase locking to pulses of unmodulated pulse trains rarely exceeded 30 pps. The strength of phase locking to frequencies ≥40 Hz often varied nonmonotonically with modulation depth, commonly peaking at modulation depths around –15 to –10 dB. Cortical phase locking coded modulation frequency reliably, whereas a putative rate code for frequency was confounded by rate changes with modulation depth. Group delay computed from the slope of mean phase versus modulation frequency tended to increase with decreasing limiting modulation frequency. Neurons in cortical extragranular layers had lower limiting modulation frequencies than did neurons in thalamic afferent layers. Those observations suggest that the low-pass characteristic of cortical phase locking results from intracortical filtering mechanisms. The results show that cortical neurons can phase lock to modulated electrical pulse trains across the range of modulation frequencies and depths presented by cochlear implant speech processors. [ABSTRACT FROM AUTHOR]

A retinal ganglion cell receptive field is made up of an excitatory center and an inhibitory surround. The surround has two components: one driven by horizontal cells at the first synaptic layer and one driven by amacrine cells at the second synaptic layer. Here we characterized how amacrine cells inhibit the center response of ON- and OFF-center Y-type ganglion cells in the in vitro guinea pig retina. A high spatial frequency grating (4–5 cyc/mm), beyond the spatial resolution of horizontal cells, drifted in the ganglion cell receptive field periphery to stimulate amacrine cells. The peripheral grating suppressed the ganglion cell spiking response to a central spot. Suppression of spiking was strongest and observed most consistently in OFF cells. In intracellular recordings, the grating suppressed the subthreshold membrane potential in two ways: a reduced slope (gain) of the stimulus-response curve by ∼20–30% and, in OFF cells, a tonic ∼1-mV hyperpolarization. In voltage clamp, the grating increased an inhibitory conductance in all cells and simultaneously decreased an excitatory conductance in OFF cells. To determine whether center response inhibition was presynaptic or postsynaptic (shunting), we measured center response gain under voltage-clamp and current-clamp conditions. Under both conditions, the peripheral grating reduced center response gain similarly. This result suggests that reduced gain in the ganglion cell subthreshold center response reflects inhibition of presynaptic bipolar terminals. Thus amacrine cells suppressed ganglion cell center response gain primarily by inhibiting bipolar cell glutamate release. [ABSTRACT FROM AUTHOR]

Extracellular recordings were obtained from single cochlear nucleus neurons in guinea pigs anesthetized with Nembutal and Hypnorm. Neurons were classified by their spontaneous firing rates and responses to acoustic stimuli. In addition, electrical shocks were applied to the midline at the level of the IVth ventricle and spike responses were recorded. Spikes were evoked by shocks only in neurons that were classified as onset choppers (O(c)). The shock-evoked spikes could be extinguished by acoustically evoked action potentials in the same neurons. In roughly 30% of the sample of O(c) neurons, quantitative aspects of the timing of this extinction were not compatible with the shock-evoked spike being antidromically conducted from O(c) output axons. Together with the presence of temporal jitter at high shock rates, the data suggest the possibility that at least some of the shock-evoked spikes may be generated by excitatory synaptic input to the O(c) neurons, most likely from the collaterals of the medial olivocochlear system (MOCS), whose axons pass close to the floor of the IVth ventricle. This excitatory synaptic input may operate to modulate the activity of O(c) neurons in addition to MOCS actions in the auditory periphery. [ABSTRACT FROM AUTHOR]

Mechanisms underlying epileptic activities recorded from entorhinal cortex (EC) were studied through a computational model based on review of cytoarchitectonic and neurobiological data about this structure. The purpose of this study is to describe and use this model to interpret epileptiform discharge patterns recorded in an experimental model of ictogenesis (guinea pig isolated brain perfused with bicuculline). A macroscopic modeling approach representing synaptic interactions between cells subpopulations in the EC was chosen for its adequacy to mimic field potentials reflecting overall dynamics rising from interconnected cells populations. Therefore intrinsic properties of neurons were not included in the modeling design. Model parameters were adjusted from an identification procedure based on quantitative comparison between real and simulated signals. For both EC deep and superficial layers, results show that the model generates very realistic signals regarding temporal dynamics, spectral features, and cross-correlation values. These simulations allowed us to infer information about the evolution of synaptic transmission between principal cell and interneuronal populations and about connectivity between deep and superficial layers during the transition from background to ictal activity. In the model, this transition was obtained for increased excitation in deep versus superficial layers. Transitions between epileptiform activities [interictal spikes, fast onset activity (25 Hz), ictal bursting activity] were explained by changes of parameters mainly related to GABAergic interactions. Notably, the model predicted an important role of GABAa,fast- and GABAb-receptor-mediated inhibition in the generation of ictal fast onset and burst activities, respectively. These findings are discussed with respect to experimental data. [ABSTRACT FROM AUTHOR]

Numerous models of the oculomotor neuronal integrator located in the prepositus hypoglossi nucleus (PHN) involve both highly tuned recurrent networks and intrinsic neuronal properties; however, there is little experimental evidence for the relative role of these two mechanisms. The experiments reported here show that all PHN neurons (PHNn) show marked phasic behavior, which is highly oscillatory in approximately 25% of the population. The behavior of this subset of PHNn, referred to as type D PHNn, is clearly different from that of the medial vestibular nucleus neurons, which transmit the bulk of head velocity-related sensory vestibular inputs without integrating them. We have investigated the firing and biophysical properties of PHNn and developed data-based realistic neuronal models to quantitatively illustrate that their active conductances can produce the oscillatory behavior. Although some individual type D PHNn are able to show some features of mathematical integration, the lack of robustness of this behavior strongly suggests that additional network interactions, likely involving all types of PHNn, are essential for the neuronal integrator. Furthermore, the relationship between the impulse activity and membrane potential of type D PHNn is highly nonlinear and frequency-dependent, even for relatively small-amplitude responses. These results suggest that some of the synaptic input to type D PHNn is likely to evoke oscillatory responses that will be nonlinearly amplified as the spike discharge rate increases. It would appear that the PHNn have specific intrinsic properties that, in conjunction with network interconnections, enhance the persistent neural activity needed for their function. [ABSTRACT FROM AUTHOR]

The inferior colliculus (IC) is a major processing center in the ascending auditory pathway. The role of the IC in the descending efferent auditory system is less clear. Although the IC central nucleus (ICC) is the major relay station for the ascending auditory pathways, the IC's cortex receives its main input from the neocortex and nonauditory sources. The goal of this study was to determine if the IC subdivisions had different functions in the descending efferent auditory system. IC subdivisions were identified by their tuning curves evoked by tone stimulation, and the effects of localized electrical stimulation on the cochlear whole-nerve action potential (CAP). Sharp tuning curves were obtained from ICC in contrast to broad tuning curves from the lateral, external cortex. Electrical stimulation within the central nucleus had a sharply tuned effect on the CAP. The frequency region affected within the cochlea closely matched the best frequency of local cells within the central nucleus. The effect of electrical stimulation within the lateral, external cortex on the CAP was smaller in comparison to central nucleus stimulation. Similar to the broad tuning of cells within the lateral cortex, electrical stimulation had a broad frequency effect on CAP thresholds. [ABSTRACT FROM AUTHOR]

Selective activation of group I metabotropic glutamate receptors (mGluRs) with (S)-3,5-dihydroxyphenylglycine (DHPG) in guinea pig hippocampal slices converts 275- to 475-ms picrotoxin-induced interictal bursts into persistent seizure-length discharges typically over 1 s in duration. Here we report that l-cysteine sulfinic acid (CSA), a sulfur-containing amino acid, prevented the induction of this persistent group I mGluR-mediated epileptiform burst prolongation. However, CSA had no effect on baseline interictal bursting activity and failed to suppress the expression of the group I mGluR-induced persistent prolonged bursts once they were fully induced. (2R,1'S,2'R,3'S)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine (PCCG-13), a selective antagonist at the phospholipase D (PLD)-coupled mGluR, had no effect of its own on DHPG-induced burst prolongation; however, CSA applied in the presence of PCCG-13 could no longer fully block the burst prolongation induced by DHPG, suggesting that CSA's antiepileptogenic effect is mediated by agonist action at this PLD-coupled receptor. These data parallel our previous data revealing that protein synthesis inhibitors prevent induction but not expression of group I mGluR-mediated persistent seizure-length discharges. Hence, PLD activation with CSA may prevent the synthesis of a protein critical for the induction of group I mGluR-mediated epileptogenesis. [ABSTRACT FROM AUTHOR]

We investigated spike-frequency adaptation of neurons sensitive to interaural phase disparities (IPDs) in the inferior colliculus (IC) of urethane-anesthetized guinea pigs using a stimulus paradigm designed to exclude the influence of adaptation below the level of binaural integration. The IPD-step stimulus consists of a binaural 3,000-ms tone, in which the first 1,000 ms is held at a neuron's least favorable ("worst") IPD, adapting out monaural components, before being stepped rapidly to a neuron's most favorable ("best") IPD for 300 ms. After some variable interval (1-1,000 ms), IPD is again stepped to the best IPD for 300 ms, before being returned to a neuron's worst IPD for the remainder of the stimulus. Exponential decay functions fitted to the response to best-IPD steps revealed an average adaptation time constant of 52.9 +/- 26.4 ms. Recovery from adaptation to best IPD steps showed an average time constant of 225.5 +/- 210.2 ms. Recovery time constants were not correlated with adaptation time constants. During the recovery period, adaptation to a 2nd best-IPD step followed similar kinetics to adaptation during the 1st best-IPD step. The mean adaptation time constant at stimulus onset (at worst IPD) was 34.8 +/- 19.7 ms, similar to the 38.4 +/- 22.1 ms recorded to contralateral stimulation alone. Individual time constants after stimulus onset were correlated with each other but not with time constants during the best-IPD step. We conclude that such binaurally derived measures of adaptation reflect processes that occur above the level of exclusively monaural pathways, and subsequent to the site of primary binaural interaction. [ABSTRACT FROM AUTHOR]